Regulation of TM4SF5-mediated tumorigenesis through induction of cell detachment and death by tiarellic acid

Abstract

mRNA for four-transmembrane L6 family member 5 (TM4SF5), a homolog of tumor antigen L6, was previously shown to be highly expressed in diverse tumors. We recently found that human hepatocarcinoma tissues also overexpressed TM4SF5 protein, in comparison to normal liver tissues. We also found that tiarellic acid (TA) caused cell detachment-related apoptosis in cells expressing endogenous or stably-overexpressing TM4SF5. When cells expressing TM4SF5 were treated with TA, we observed reduced phosphorylation of focal adhesion kinase, paxillin, and p130Cas, but not c-Src. TA treatment also caused focal adhesion loss and reduced cell adhesion, and increased the numbers of floating cells and apoptotic cells. These effects were blocked by overexpression of focal adhesion molecules, suggesting that treatment with TA mediates anoikis of TM4SF5-expressing cells. However, TM4SF5-null cells were not affected by TA, indicating that these effects occur specifically in TM4SF5-positive cells. TA administration reduced tumor formation in nude mice injected with TM4SF5-expressing cells, presumably through increased apoptosis in TM4SF5-positive tumors. These observations indicate that TM4SF5-positive tumorigenesis can be inhibited by TA via induction of cell detachment-related apoptosis, and suggest that TA may be developed as a putative therapeutic reagent against TM4SF5-positive tumorigenesis.